MOLECULAR EPIDEMIOLOGY OF ALCOHOLISM AND COMORBID DISORDERS This MARC research project, project 5, seeks to build upon gene-discovery projects such as COGA (Collaborative Study on the Genetics of Alcoholism: PI, Porjesz) and similar projects (e.g. Pis Hill, Kendler) which are studying treatment-ascertained alcoholics and their relatives, and the MARC-affiliated Alcohol-QTL IRPG consortium (Pis Heath, Martin, Madden, Todd), which is studying community-ascertained alcoholics and heavy smokers and their adult relatives, by incorporating a molecular genetic component into 5 prospective longitudinal studies (Pis Anokhin, Bucholz, Chassin, Heath, Sher: ABCHS Cohorts) spanning the age-range from early adolescence into young adulthood. In addition to completing DNA collection on the Heath cohort (years 1-2), this research project will conduct genotyping for a limited number of candidate genes (years 1-2);and DNA array genetic association analysis (years 3-5). We focus on a limited number of candidate phenotypes where prospective data are expected to be informative for understanding the etiology of alcoholism. The selection of the first candidate phenotypes and candidate genes is guided by the MARC focus on the roles of overlapping mechanisms of behavioral under-control, negative affect regulation and pharmacologic vulnerability in the etiology of alcohol use disorders (AUDs), emphasizing AUD phenotypes associated with (a) externalizing symptoms, (b) tolerance and quantitative consumption indices, (c) cooccurrence with tobacco dependence, and (d) negative affect. The second set of candidate genes will be selected from replicated genome-wide association (GWA) study results from COGA, Australian IRPG and other studies.